In the last 20 years, HIV infection has clearly become a major health concern. There are significant sex differences in the development and progression of AIDS. Women seroconvert at a lower viral load, fail to progress during pregnancy, often have gonadal dysfunction, and develop HIV associated dementia (HAD) twice as often as men. HAD occurs in approximately 15-30% patients with advanced HIV disease and is caused by neurodegeneration in the hippocampus, basal ganglion and cortex. Furthermore, older HIV infected individuals are more likely to have HAD as compared to younger patients. While HIV does not infect neurons directly, it can induce neurotoxicity from infected astrocytes and microglia. The virus sheds proteins (Tat and gp120) that have direct neurotoxic effects. These proteins are believed to cause neuronal cell death by initiating oxidative damage resulting in apoptosis. While clinical studies are limited, it has been shown that older women were less likely to develop HAD if they were on hormone replacement therapy as compared to those who were not. This study was small, but suggests that estrogen is an important component in the development of HAD. The proposed studies will test the hypothesis that 17beta-estradiol prevents neuronal cell death in a cortical explant model following exposure to toxic HIV proteins by suppressing apoptotic signals. The specific aims are as follows: Aim 1. To determine the characteristics of cell death following HIV protein administration in vitro. These experiments will establish cortical explant cultures as a model to study the neurotoxic actions of HIV proteins. We will perform dose response and time-course experiments to further determine the evolution of cell death following HIV protein administration. Furthermore, we will determine if cell death induced by HIV proteins occurs by apoptosis. Aim 2. To determine if 17-beta-estradiol prevents cell death following HIV protein toxicity. In these experiments, we will determine under what treatment paradigms 17beta-estradiol prevents Tat1-72 induced toxicity. In addition, we will determine if the estrogen receptor is required for this protection by the addition of an estrogen receptor antagonist. Finally, we will examine the interaction between 17beta-estradiol and apoptotic cellular signaling pathways. The studies outlined here will be critical to our understanding of the mechanisms by which estrogen protects the brain against HIV protein neurotoxicity. Understanding the mechanisms of estrogen action in a tissue specific manner is important to eventually designing estrogen therapies that target specific tissues while avoiding negative actions of estrogen in other tissues.